DESCRIPTION (Applicant's abstract): Apoptosis refers to a cellular suicide program employed as part of normal development or in response to cellular injury, as seen in neurodegenerative and ischemic diseases. Caspases are a family of cysteine proteases represented by interleukin 1^D-converting enzyme (ICE), and are distal elements in the apoptotic pathway. They mediate irreversible cellular damage through proteolytic cleavage of specific substrates, but little is known regarding the specific settings in which they are activated or how they are regulated. We propose to test the central hypothesis that within the CNS, caspase activation is dependent upon the developmental stage of the neuron, the specific cytotoxic stimulus it receives, and the upstream signal provided by the proapoptotic gene Bax. We will determine if caspases are regulated in a developmental and injury-dependent manner by measuring caspase activity in embryonic and postnatal neuronal cultures, in response to diverse cellular insults. We will determine if Bax is an upstream regulator of caspases, by measuring caspase activity in wild-type and Bax deficient neuronal cultures, in response to diverse death stimuli. Elucidation of cell death regulatory pathways will delineate targets for selective therapeutic intervention in the treatment of diseases where apoptosis plays a role.